The goal of these studies is to explore the efficacy, toxicity, and mechanisms of action of new treatments for dermatologic diseases, particularly, skin cancer and the disorders of keratinization. During the last decade over 300 patients studied have established the efficacy and characterized the toxicity of isotretinoin and etretinate in the treatment of a variety of disorders. Patients requiring long-term retinoid therapy continue to be monitored. Skeletal toxicity is an important chronic side effect. The high rate of peripheral skeletal involvement that occurs after chronic etretinate therapy was first identified in these patients. In patients with Darier's disease, we have identified and are characterizing a novel, common, cystic bone abnormality. Peptide T is a synthetic oligopeptide which has been associated with improvement in HIV related psoriasiform eruptions. After an initial clinical trial of intranasal Peptide T for psoriasis showed minimal efficacy, a topical study was begun. We are expanding our studies directed at skin cancer treatment and prevention . We demonstrated the effectiveness of oral iostretinoin as a chemopreventive agent in patients with high rates of skin cancer formation. These patients are now maintained on long-term isotretinoin for chemoprevention. A phase I/II study of recombinant human interferon gamma for basal cell carcinoma is ongoing. All 6 tumors treated to date have become smaller; 2 underwent complete histological regression. In collaboration with Allen Bale we have identified that a mutation in a tumor suppressor gene is the probable cause of the nevoid basal cell carcinoma (Gorlin's) syndrome and demonstrated tight linkage of the syndrome gene to this region. Our collaborative study with Sherri Bale and Peter Steinert, has successfully identified linkage of the epidermolytic hyperkeratosis gene to the type II keratin gene cluster on chromosome 12q. These studies are continuing.